Acid-base balance in KDs: mechanisms and clinical relevance

The KD induces a metabolic state known as ketogenesis, characterized by the production of ketone bodies, including acetoacetate, β-hydroxybutyrate, and acetone [6]. While ketones provide an efficient alternative fuel source in the absence of glucose, they are inherently acidic [11]. As ketone body concentrations rise in the blood, they increase the systemic acid load, resulting in a physiological state called nutritional ketosis [12]. Although nutritional ketosis is often associated with therapeutic benefits in conditions such as epilepsy, obesity, and type 2 diabetes, sustained elevations in acidic metabolites can overwhelm the body’s natural buffering systems, including bicarbonate, phosphate, and protein buffers [13, 14]. When the acid load exceeds buffering capacity, systemic acidosis can occur, with several downstream effects on bone, muscle, renal, and metabolic health [15]. Bone demineralization may develop as the skeleton serves as a reservoir of alkaline minerals [16]; calcium is mobilized from bone to buffer excess hydrogen ions, increasing the risk of reduced bone mineral density and osteoporosis over time [17]. Muscle cramps and fatigue are common due to electrolyte disturbances, particularly losses of potassium and magnesium [18]. Renal function may also be adversely affected, as the KD can exacerbate metabolic acidosis by increasing the DAL and enhancing endogenous acid production through fatty acid oxidation. Moreover, it has been linked to a higher risk of kidney stone formation in patients [19]. In addition, chronic low-grade acidosis can impair enzymatic reactions and metabolic pathways, potentially compromising glucose metabolism, lipid metabolism, and overall cellular function [20]. The digestive system also responds negatively to an excess of unbuffered acidic substances, presenting with a variety of symptoms such as nausea, vomiting, heartburn, diarrhea, and halitosis. At the cardiac level, increased heart rate and alterations in cardiac rhythm may occur. Recent studies underscore the importance of monitoring acid-base balance in individuals on KD, not only to optimize metabolic benefits but also to prevent complications. Side effects such as nephrolithiasis, muscle cramps, and bone loss are among the most frequently reported and should be anticipated in clinical practice [15, 21].

The role of alkalinizing salts in modulating systemic acidosis during ketosis

Ketone bodies, including acetoacetate, β-hydroxybutyrate, and acetone, are produced primarily in the liver during periods of carbohydrate restriction or prolonged fasting, such as those observed in KDs. When glucose availability is limited, the body increases fatty acid mobilization from adipose tissue, which is then transported to the liver. These fatty acids undergo β-oxidation to generate acetyl-CoA, the central molecule in ketone body synthesis. High levels of acetyl-CoA promote the condensation of two molecules of acetyl-CoA to form acetoacetate, which is subsequently converted into β-hydroxybutyrate under the influence of NADH [22]. Acetoacetate can also decarboxylate spontaneously to form acetone, which is exhaled. This shift towards ketone body production results in an increased production of acidic byproducts. Specifically, β-hydroxybutyrate and acetoacetate are weak acids, and their accumulation leads to a decrease in plasma pH, contributing to a mild form of metabolic acidosis. This is particularly significant in individuals following KDs, where the ratio of ketone bodies to blood glucose increases substantially, driving the systemic acid load.

Alkalinizing salts, such as potassium bicarbonate, potassium citrate, and magnesium citrate, act to counteract this acidotic state by increasing the bicarbonate buffering capacity of the body [23]. This buffering mechanism helps to stabilize the pH, preventing a significant drop in blood pH (metabolic acidosis) [24].

The efficacy of alkalinizing salts in mitigating this acidosis has been supported by experimental studies. For example, studies examining the administration of potassium bicarbonate and potassium citrate have demonstrated their ability to reduce the systemic effects of chronic metabolic acidosis by enhancing the body’s buffering capacity [25, 26]. These studies suggest that alkalinizing salts can neutralize the excess acid generated during ketogenesis, thus preserving bone health and improving overall metabolic parameters. However, while these studies provide strong evidence for the general benefits of alkalinizing salts in mitigating systemic acidosis, the specific effects in ketogenic populations remain less well defined. The literature is currently limited by a lack of direct studies on the role of alkalinizing salts in KDs, particularly in terms of their ability to modulate blood pH and support acid-base balance in individuals undergoing ketosis, where pH tends to remain stable but at the expense of depleting alkaline reserves from bone and muscle tissues.

Given the potential impact of alkalinizing salts in counteracting the acidotic effects of ketone body production, further research is needed to establish their precise role in ketogenic populations. Clinicians should be aware of the potential for alkalinizing salts to act as adjunctive treatments in mitigating the mild metabolic acidosis often observed in individuals following KDs, particularly in populations at risk for osteoporosis, kidney stones, and other complications associated with chronic metabolic acidosis.

Broader dietary and supplemental interventions for managing acid load

To counteract the acidogenic effects of KDs and modern Western dietary patterns, both supplementation and dietary strategies have been proposed. Alkalinizing salts, including sodium bicarbonate, potassium citrate, magnesium citrate, calcium carbonate, and potassium bicarbonate, play distinct roles in acid-base regulation.

Sodium bicarbonate is a highly soluble compound that rapidly neutralizes excess hydrogen ions in the extracellular space, restoring systemic pH toward normal [27]. Potassium citrate serves a dual function: it not only provides an alkaline load but also reduces urinary calcium excretion and acidification, lowering the risk of kidney stones [28]. Magnesium and calcium salts help correct acid-induced mineral losses; calcium, in particular, offsets bone resorption, while magnesium supports hundreds of enzymatic reactions essential for neuromuscular function [29–31]. Potassium, whether supplied as citrate or bicarbonate, is crucial for intracellular buffering and cardiac function, especially since KD increases urinary potassium losses [32, 33] (Figure 1).

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Figure 1. Ketone body production and the role of alkalinizing salts in counteracting metabolic acidosis.

Clinical evidence suggests that alkalinizing salts can mitigate several KD-related complications, including bone demineralization, muscle cramps, and nephrolithiasis [8, 19, 34, 35]. They may also improve mineral balance and cardiovascular stability [36]. Natural sources such as bicarbonate-calcium mineral water provide additional alkalinity and calcium to support skeletal health [11, 37].

However, these interventions must be individualized. Excessive intake can lead to hypernatremia, hyperkalemia, alkalosis, gastrointestinal upset, or hypercalcemia [38–40]. Therefore, careful dosing and regular monitoring of electrolyte status are essential [41, 42].

Summary of reviewed evidence

To synthesize the evidence on alkalinizing salt use in ketogenic therapies, we conducted a comprehensive literature review covering studies published from 2000 to 2024 in PubMed, Scopus, and Google Scholar. Search terms included “alkalinizing salts”, “ketogenic diet”, “acid-base balance”, “mineral supplementation”, and individual compounds such as “sodium bicarbonate”, “potassium citrate”, “magnesium citrate”, and “calcium carbonate”. We prioritized peer-reviewed human studies that investigated the effects of mineral supplementation on acid-base balance, bone health, or kidney function. Studies were included if they involved adult populations and reported specific outcomes relevant to ketogenic dietary protocols. Exclusion criteria comprised pediatric studies, animal models, non-interventional reviews, and articles not addressing ketogenic or acid-base-related outcomes. After screening 48 articles, seven were selected for in-depth analysis and are summarized in Table 1.

These studies collectively highlight the growing recognition of alkalinizing salt supplementation, particularly during KD therapies, as a vital strategy to maintain acid-base balance and prevent the metabolic complications that can arise due to the acidic nature of ketosis. Table 1 summarizes key narrative reviews, case report, and overview articles relevant to DAL, KD therapies, and metabolic health outcomes. The selected papers provide context for understanding the mechanisms of acid-base regulation, clinical consequences of acidogenic diets, and the potential role of alkalinizing interventions across different populations.

Human studies on mineral supplementation

Several studies have highlighted the significance of dietary and supplemental interventions to counteract the effects of CSSMA, particularly through the alkalinization of the body. The Western diet, often characterized by high consumption of acid-forming foods (such as animal proteins, refined sugars, and processed foods) and low intake of base-forming minerals (abundant in fruits and vegetables), has been strongly associated with chronic low-grade metabolic acidosis. As noted by Naude [20], one of the most effective strategies for neutralizing the effects of an acidogenic diet is increasing the intake of alkaline foods, such as fruits and vegetables, which are rich in base-forming minerals like potassium, magnesium, and calcium. This dietary modification helps shift the body’s acid-base balance toward a more alkaline state, counteracting the acidosis induced by modern eating habits.

Beyond dietary changes, supplementation with alkalinizing minerals such as potassium citrate, potassium bicarbonate, calcium carbonate, and magnesium citrate has shown considerable promise in reducing the systemic effects of metabolic acidosis, particularly in relation to bone health and kidney function. Numerous clinical trials have demonstrated the efficacy of these supplements in improving metabolic parameters and mitigating the negative effects of chronic acid load on the body.

Potassium citrate supplementation has been extensively studied for its ability to neutralize systemic acidity and support bone health. A landmark study by Sellmeyer et al. [25] administered 90 mmoL/day (approximately 9,733 mg/day) of potassium citrate to postmenopausal women and observed significant improvements in bone density. In line with these findings, Moseley et al. [32] tested higher doses of potassium citrate, ranging from 60–90 mmoL/day (6,480–9,733 mg/day), in older adults. This supplementation helped maintain bone mineral density and reduced urinary calcium excretion, suggesting that potassium citrate could be a therapeutic agent for populations at risk of osteoporosis and bone mineral loss. Potassium bicarbonate has also been shown to counteract bone demineralization. Frassetto et al. [26] and Dawson-Hughes et al. [33] found that doses of 30–90 mmoL/day were effective in preserving bone mineral density in postmenopausal women and older adults, while Sebastian et al. [50] reported that 60–120 mmoL/day significantly reduced DAL and helped prevent bone demineralization.

Magnesium and calcium supplementation also play an important role in mitigating the effects of acid retention. Magnesium, a critical cofactor in numerous enzymatic reactions, is essential for maintaining muscle function and electrolyte balance. Supplementation with magnesium citrate has been shown to alleviate symptoms such as cramps and fatigue, which are commonly experienced in ketogenic dietary regimens. Calcium carbonate, in turn, supports bone health by buffering systemic acidity and reducing the need for calcium mobilization from bone stores. Domrongkitchaiporn et al. [51] demonstrated that calcium supplementation, in combination with alkalinizing agents, helped preserve bone mineral density and reduced the risk of fractures in individuals experiencing chronic acidosis.

In a study by Maurer et al. [52], the administration of a combination of sodium bicarbonate and potassium bicarbonate at 0.55 mmoL/kg body weight resulted in improved metabolic parameters and significant reductions in the body’s acid load. These findings support the utility of sodium bicarbonate as an adjunct strategy to restore acid-base balance in patients with metabolic acidosis.

In addition to skeletal outcomes, potassium citrate has shown specific benefits for kidney health and the prevention of nephrolithiasis. For example, McNally et al. [53] evaluated the effects of 2 mEq/kg/day of potassium citrate in children undergoing KD therapy and observed a significant reduction in urinary acid excretion, a major risk factor for kidney stone formation. Carvalho et al. [54] reported that a dose of 55 mEq/day of potassium citrate, administered to adults after lithotripsy, reduced urinary acidity and significantly lowered the recurrence rate of kidney stones.

The collective evidence from these studies indicates that alkalinizing minerals, including potassium citrate, potassium bicarbonate, magnesium citrate, calcium carbonate, and sodium bicarbonate, are effective in neutralizing the systemic effects of chronic metabolic acidosis, preserving bone health, and supporting renal function. These supplements may serve as essential components of clinical strategies to manage acid-base disturbances, particularly in aging populations, individuals following KDs, and patients at risk for nephrolithiasis or osteoporosis. Moreover, increased consumption of fruits and vegetables rich in base-forming minerals is strongly recommended as a complementary dietary measure.

However, it should be noted that much of the available evidence derives from studies conducted in the general population rather than in individuals following KDs. Further research is needed to directly assess the efficacy and safety of alkalinizing salt supplementation within ketogenic dietary protocols. In addition to the narrative and clinical reviews summarized in Table 1, we also examined a series of experimental studies that directly investigated the effects of alkalinizing mineral supplementation on acid-base balance, bone health, and renal outcomes in adult populations. These studies, summarized in Table 2, provide quantitative evidence to support the proposed supplementation guidelines and contextualize the clinical recommendations discussed.

Clinical recommendations and practical considerations

Based on the above evidence and the authors’ clinical experience, we propose tentative guidelines for alkalinizing salt use in adults on KD (Table 3). These include recommended dosages, frequencies, and monitoring parameters for sodium bicarbonate, potassium citrate, magnesium citrate, calcium carbonate, and bicarbonate-calcium mineral water. These guidelines are preliminary and drawn primarily from general dietary studies, with supporting data from two pilot interventions in psoriasis and fibromyalgia patients undergoing ketogenic protocols [55, 56].

Limitations and future research

By integrating alkalinizing salts and mineral-rich water into the ketogenic regimen, individuals can not only optimize their metabolic health but also minimize potential side effects such as osteoporosis, kidney stones, and systemic inflammation associated with sustained acidogenic dietary patterns.

Although the hypothesis that ketosis may lead to metabolic acidosis and its related complications is supported by physiological models and preliminary evidence, several important limitations persist in the current literature. First, there is a lack of direct clinical studies specifically assessing the impact of KDs on acid-base homeostasis and its consequences on bone, muscle, and renal health. Most of the available data come from observational or short-term interventional studies that are not exclusively conducted in ketogenic populations.

Additionally, the majority of existing trials evaluating the use of alkalinizing salts are of limited duration. Consequently, the long-term effects of these interventions, especially on skeletal integrity, muscular performance, and kidney function, remain insufficiently characterized. Compounding this issue is the small sample size of many published studies, which restricts the ability to generalize the findings to broader clinical populations. Furthermore, variability in supplementation protocols, such as inconsistent dosages and salt formulations, makes it difficult to determine the most effective strategies for mitigating acidosis in individuals adhering to KDs.

To advance the field and develop evidence-based recommendations, several areas warrant focused research. Well-designed, long-term randomized controlled trials (RCTs) are needed to investigate the efficacy and safety of alkalinizing salt supplementation in people following KDs. These trials should evaluate comprehensive outcomes, including biochemical markers of acidosis, bone mineral density, muscular function, and renal parameters.

Future studies should also aim to include larger and more diverse populations, including individuals with metabolic comorbidities such as obesity, type 2 diabetes, and early-stage renal impairment. This will enhance the external validity of findings and help identify subgroups that may particularly benefit from supplementation.

Equally important is the need for standardized supplementation protocols. Establishing optimal dosing regimens and selecting the most appropriate alkalinizing agents will allow for consistency across clinical studies and improve the formulation of practical clinical guidelines. Mechanistic studies should also be prioritized to elucidate how alkalinizing salts modulate acid-base regulation and influence physiological systems such as bone remodeling, electrolyte homeostasis, and renal filtration.

Finally, clinical research should incorporate structured monitoring strategies to assess the safety and effectiveness of supplementation. This includes tracking changes in mineral balance, acid-base biomarkers, kidney function, and patient-reported outcomes. The development of clear clinical protocols will support healthcare professionals in managing ketogenic regimens while minimizing risks associated with acid retention.

In conclusion, targeted, high-quality research is essential to clarify the role of alkalinizing salts in ketogenic therapy. Addressing these limitations will contribute to the development of robust, individualized supplementation guidelines aimed at optimizing metabolic outcomes and reducing complications in this growing patient population.